DESCRIPTION: (Applicant's Abstract) Two lines of evidence have suggested that inflammatory mechanisms may play a pivotal role in the pathogenesis of Alzheimer's disease (AD): 1) immunocytochemical studies have demonstrated that the close association of activated microglia with mature senile plaques, one of the neuropathological hallmarks of AD, and the presence of complement and acute phase proteins within amyloid plaques and, 2) retrospective epidemiological studies have revealed an inverse relationship between anti-inflammatory drug use and AD. These findings are consistent with the known response of microglia to neuronal insults in performing macrophage and immune functions such as phagocytosis and secretion of nitric oxide (NO) and superoxide anions. Whether the proliferation of activated microglia contributes and/or is a response to the neurodegenerative and inflammatory mechanisms in the disease is not clear at present. Recent studies demonstrating specific cholinergic muscarinic receptor-mediated increases of intracellular Ca++ in cultured microglial cells and the presence of the unique m5 receptor subtype on microglia, suggest that microglial activation may be regulated, at least in part, by neurotransmitters. These data, taken together with the demonstrated close association of microglia, with basal forebrain cholinergic neurons, suggest a provocative relationship between diminished cholinergic neurotransmission in AD and microglial activation and/or dysfunction. The overall goal of this proposal is to improve our understanding of cholinergic neuron-microglia communication. To this end, the specific aims of this application are: 1) to characterize the muscarinic receptor subtype(s) on cultured microglia and determine the second messenger responses and functional consequences of muscarinic receptor activation on microglia, 2) to further characterize our preliminary findings demonstrating diminished m1 receptor activation by microglial secreted factors, 3) to test the hypothesis that altered m1 muscarinic receptor function in AD Z(for review, see Flynn, et all, 1995) may result from oxidation of receptor i3-loop vicinal thiol groups, and the hypothesis that microglia may contribute to altered m1 foundation by secretion of nitric oxide (NO), and 4) to compare muscarinic receptor mediated-responses on isolated microglia from normal and AD brains. The results of these studies will enhance our understanding of putative neurotransmitter regulation of microglia, suggest a possible mechanism for the loss of m1 muscarinic receptor responsiveness in AD and the relative ineffectiveness of cholinergic replacement therapies used to date for the treatment of AD, and support the rationale for the use of anti-inflammatory drugs for the treatment of AD.